A number of 3-aryl substituted oxindole compounds are described by P. Hewawasam et al. in U.S. Pat. Nos. 5,565,483 and 5,602,169, issued Oct. 15, 1996 and Feb. 11, 1997, respectively, which are useful for the treatment of disorders responsive to modulation of the large conductance calcium-activated (Maxi-K) channels, and having the general formula ##STR2## wherein R is defined as hydrogen, hydroxy or fluoro. The compounds described by P. Hewawasan et al. are generally prepared by well-known procedures employing the use of isatins as intermediates. An alternative route via cyclization of an anilino-ester intermediate for the preparation of compounds wherein R is hydrogen is also described.
Since the general method produces a racemic mixture of compounds, there is also described a method for the stereospecific insertion of a 3-hydroxy moiety via selective oxidation with the appropriate chiral oxidizing agent to provide compounds having the (3R) or (3S) configuration. However, in the instance wherein R is fluoro and the fluorination is carried out with diethylaminosulfur trifluoride (DAST) a racemic mixture of 3-fluoro 3-aryl substituted oxindoles are described and separation of the enantiomeric forms of the compound is achieved by the separation of the racemic mixture using high pressure liquid chromatography. The separation of enantiomers by chiral column chromatography is not an efficient process, especially on a commercial scale for the preparation of a single enantiomer.
The present inventors have now found a simple, convenient and economical chiral process for the preparation of substantially pure enantiomers of 3-fluoro substituted 3-aryl oxindoles and to certain chiral intermediates thereof.